Is cyclosporin (CsA) safe to use during pregnancy?

Cyclosporine in Pregnancy

Direct Answer

Cyclosporine can be safely used during pregnancy when clinically necessary, as it does not appear to be teratogenic, though it is associated with increased rates of prematurity and requires careful monitoring for hypertension and preeclampsia. 1, 2

Safety Profile

Teratogenicity and Malformations

• Cyclosporine is not a major human teratogen based on extensive experience in transplant recipients and patients with autoimmune conditions. 2, 3

• No specific birth defects or pattern of malformations have been linked to cyclosporine exposure during pregnancy. 2

• A meta-analysis of 410 patients found an overall malformation rate of 4.1%, which does not vary substantially from the general population (2-4%). 3

• The calculated odds ratio of 3.83 for malformations did not achieve statistical significance (95% CI 0.75-19.6). 3

• The National Transplantation Pregnancy Registry (NTPR) including 622 pregnancies found that the overall rate of major birth defects, live birth rates, and miscarriage rates were comparable to the general population. 4

Pregnancy Complications

Prematurity is the primary concern with cyclosporine use during pregnancy:

• Increased rates of prematurity have been consistently observed, with an overall prevalence rate of 56.3% in one meta-analysis. 2, 3

• The odds ratio for prematurity was 1.52 (95% CI 1.00-2.32), approaching but not reaching statistical significance. 3

• Lower birth weight is commonly reported, with an odds ratio of 1.5 (95% CI 0.95-2.44). 3

Maternal complications include:

• Hypertension occurs in approximately 20% of patients on cyclosporine. 2, 5

• Preeclampsia rates appear elevated, though this may be confounded by underlying maternal conditions. 2, 4

• Gestational diabetes mellitus is reported at higher incidences than the general population. 6

Guideline-Based Recommendations by Condition

Systemic Lupus Erythematosus (SLE)

• The European League Against Rheumatism (EULAR) considers cyclosporine compatible with pregnancy and includes it among medications that can be continued during pregnancy. 1, 2

• Uncontrolled studies suggest an acceptable benefit/risk ratio of calcineurin inhibitors (ciclosporin A, tacrolimus) in controlling SLE activity during pregnancy. 1

• In a study of 21 patients with systemic autoimmune diseases (including 14 with SLE) treated with cyclosporine throughout 29 gestations, the live birth rate was 86.2% with disease flares in only 4% during gestation. 7

Inflammatory Bowel Disease (IBD)

• For acute severe ulcerative colitis, cyclosporine can be used during pregnancy when needed for severe disease. 1

• Cyclosporine exposure has not been shown to increase fetal malformation in solid organ transplantation and case series in IBD. 1

• Cyclosporine exposure has been associated with premature delivery and low birth weight, potentially confounded by disease severity. 1

• Gestational hypertension, diabetes, and pre-eclampsia rates are not increased specifically in IBD patients. 1

Organ Transplantation

• Discontinuation of necessary immunosuppression during pregnancy may lead to transplant rejection, which could pose greater risks to both mother and fetus than continuing treatment. 2

• Cyclosporine levels tend to decline during pregnancy, requiring dose adjustments to maintain therapeutic levels. 8

Monitoring Requirements During Pregnancy

Blood pressure monitoring is critical:

• Regular blood pressure monitoring is essential, as cyclosporine-induced hypertension occurs in approximately 20% of patients. 2, 5

• Early morning resting blood pressure is a more sensitive indicator of early nephrotoxicity than elevated creatinine. 2, 9

• If hypertension develops, consider dose reduction of cyclosporine. 2, 5

Preferred antihypertensive management:

• Calcium channel blockers (nifedipine, isradipine, felodipine, or amlodipine) are the preferred antihypertensive agents as they are nephroprotective and do not interact with cyclosporine metabolism. 2, 5

Cyclosporine level monitoring:

• Mean cyclosporine levels tend to decline during pregnancy, with five of six patients in one study showing declines after adjusting for dose. 8

• Therapeutic drug monitoring should be performed regularly to maintain adequate immunosuppression. 8

Breastfeeding Considerations

Breastfeeding while on cyclosporine requires careful consideration:

• Cyclosporine passes into breast milk and contains ethanol that will be orally absorbed by the nursing infant. 2, 9

• A decision should be made whether to discontinue breastfeeding or discontinue cyclosporine based on the importance of the drug to the mother. 2

• One case reported therapeutic blood concentrations in a breastfed infant without adverse effects, though other studies have not reported associated issues. 1

Important Caveats

Pre-pregnancy counseling is essential:

• Women should be informed of the risks associated with cyclosporine during pregnancy before starting therapy, including increased rates of prematurity and potential for hypertension. 2

• The decision to use cyclosporine during pregnancy should involve careful consideration of the risk-benefit ratio. 2

Confounding factors:

• Many adverse outcomes attributed to cyclosporine may be confounded by underlying maternal disease severity, comorbidities, and concomitant medications. 4, 6, 3

• Patients receiving cyclosporine during pregnancy have underlying medical conditions that limit the interpretability of findings regarding adverse outcomes. 4

FDA classification:

• Cyclosporine is classified as FDA pregnancy category C, meaning it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 2